# US 2014/0155330 A1 · Compositions And Methods For Modulating Apoptosis

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- Number: US 2014/0155330 A1
- Document ID: US20140155330A1
- Status: Published application
- Kind: A1
- Application number: 14/177,840
- Filed: 2014-02-11
- Published: 2014-06-05
- Earliest claimed: 2011-08-11
- Assignees: Yeda Research and Development Co. Ltd.
- Applicants: Yeda Research and Development Co. Ltd.
- Inventors: Adi Kimchi; Assaf Rubinstein
- Web page: https://patentgrep.com/patent/US20140155330A1

## CPC

- C07K 14/4747: {Apoptosis related proteins}
- G01N 33/566: using specific carrier or receptor proteins as ligand binding reagents {where possible specific carrier or receptor proteins are classified with their target compounds}
- G01N 33/57575: {involving oncogenic proteins}
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Peptides, compositions and methods for modulating apoptosis, useful for treating diseases or disorders characterized by dysregulated apoptosis, such as cancer or neurodegenerative diseases. Screening methods for identifying agents that mediate apoptosis by regulating Atg12 binding to Bcl-2 family members.

## Claims

### Claim 1

An isolated peptide comprising an amino acid sequence having no more than 30 amino acids as set forth in SEQ ID NO: 1 (IDILLKAVGDTP), or an analog or derivative thereof.

### Claim 2 (depends on 1)

The isolated peptide of claim 1, wherein the isolated peptide consists of no more than 25 amino acids, no more than 20 amino acids or no more than 15 amino acids.

### Claim 3 (depends on 1)

The isolated peptide of claim 1, wherein the isolated peptide consists of SEQ ID NO: 1.

### Claim 4 (depends on 1)

The isolated peptide of claim 1, wherein the analog has at least 70% sequence identity to SEQ ID NO: 1.

### Claim 5 (depends on 4)

The isolated peptide of claim 4, wherein the analog has the amino acid sequence selected from the group consisting of: SEQ ID NO: 3 (IDVLLKAVGDTP), SEQ ID NO: 5 (IDVLLKAVGDDP) and SEQ ID NO: 6 (IDVLLKAVGDEP).

### Claim 6 (depends on 1)

The isolated peptide of claim 1, wherein said peptide binds a Bcl-2 anti-apoptotic protein, or wherein said peptide is a pro-apoptotic peptide.

### Claim 7 (depends on 6)

The isolated peptide of claim 6, wherein said peptide binds the BH3 binding pocket of the Bcl-2 anti-apoptotic protein.

### Claim 8 (depends on 6)

The isolated peptide of claim 6, wherein the Bcl-2 anti-apoptotic protein is selected from the group consisting of: Bcl-2, Bcl-XL, Bcl-w, Bcl-B, Mcl-1 and A1 (Bfl-1).

### Claim 9 (depends on 8)

The isolated peptide of claim 8, wherein the Bcl-2 anti-apoptotic protein is Bcl-2 or Mcl-1.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising the isolated peptide of claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

A method for inducing apoptosis in a cell, the method comprising contacting the cell with the peptide of claim 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein said cell is a cancer cell.

### Claim 13 (depends on 10)

A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 10.

### Claim 14 (depends on 13)

The method of claim 13, wherein the peptide sensitizes cancer cells to chemotherapy treatment or wherein the method further comprises administering to the subject a chemotherapeutic agent.

### Claim 15 (depends on 14)

The method of claim 14, wherein the chemotherapeutic agent is an apoptosis-inducing chemotherapeutic agent or wherein the cancer is selected from a hematopoietic malignancy, a solid malignancy and a chemoresistant cancer.

### Claim 16 (depends on 15)

The method of claim 15, wherein the cancer is a hematopoietic malignancy selected from the group consisting of: acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma or wherein the cancer is a solid malignancy selected from the group consisting of: prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, head and neck cancer, kidney cancer, ovarian cancer, cervix cancer, bone cancer, liver cancer, thyroid cancer and brain cancer.

### Claim 17 (depends on 13)

The method according claim 13, wherein the subject is a mammal or a human.

### Claim 18

A method of screening for a pro-apoptotic agent, the method comprising the steps of:
exposing a cell expressing Atg12 and a Bcl-2 anti-apoptotic protein to a putative pro-apoptotic agent; and
determining the binding of Atg12 to the Bcl-2 anti-apoptotic protein;
wherein enhancement of said binding indicates that the agent is a pro-apoptotic agent.

### Claim 19 (depends on 18)

The method of claim 18, further comprising the step of:
determining the change in survival of the cell in the presence of the agent relative to a control.

### Claim 20 (depends on 18)

The method of claim 18, wherein the Bcl-2 anti-apoptotic protein is selected from the group consisting of: Bcl-2, Bcl-XL, Bcl-w, Bcl-B, Mcl-1 and A1 (Bfl-1) and wherein the putative agent is selected from the group consisting of: peptides, nucleic acids, organic molecules, inorganic compounds and antibodies or antigen binding fragments thereof.

### Claim 21 (depends on 18)

A pro-apoptotic agent obtained by the method according to claim 18.

### Claim 22

A method of screening for an anti-apoptotic agent, the method comprising the steps of:
exposing a cell expressing Atg12 and a Bcl-2 anti-apoptotic protein to a putative anti-apoptotic agent; and
determining the binding of Atg12 to the Bcl-2 anti-apoptotic protein;
wherein reduction of said binding indicates that the agent is an anti-apoptotic agent.

### Claim 23 (depends on 22)

The method of claim 22 further comprising:
determining the change in survival of the cell in the presence of the agent relative to a control, or wherein the putative agent is selected from the group consisting of: peptides, nucleic acids, organic molecules, inorganic compounds and antibodies or antigen binding fragments thereof.

### Claim 24 (depends on 22)

An anti-apoptotic agent obtained by the method according to claim 22 or a pharmaceutical composition comprising said anti-apoptotic agent as an active ingredient, and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 24)

A method for treating a disease or disorder characterized by excessive cellular death in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the anti-apoptotic agent of claim 24.

### Claim 26 (depends on 25)

The method of claim 25, wherein the disease or disorder characterized by excessive cellular death is a neurodegenerative disease or wherein the disease or disorder is associated with neuronal cell death.

### Claim 27 (depends on 26)

The method of claim 26, wherein the disease or disorder is a neurodegenerative disease selected from the group consisting of: Alzheimer's disease, Huntington's disease, Parkinson's disease, neurodegeneration due to stroke, amyotrophic lateral sclerosis (ALS), Pick's disease, Progressive Supranuclear Palsy (PSP), fronto-temporal dementia (FTD), pallido-ponto-nigral degeneration (PPND), Guam-ALS syndrome, pallido-nigro-luysian degeneration (PNLD) and cortico-basal degeneration (CBD), or wherein the disease or disorder is associated with neuronal cell death and is selected form the group consisting of: epilepsy, hypoxia/ischemia related acute brain injury, Parkinson's disease and Alzheimer's disease.